1. Field of the Invention
The invention relates to N,N'-bis(sulfonyl)hydrazines, and more particularly to alkoxy- and aryloxycarbonyl derivatives of N,N'-bis(sulfonyl)hydrazines that have antineoplastic activity.
2. Brief Description of the Art
Solid tumors have been difficult to treat by chemotherapeutic and radiotherapeutic approaches. Inefficient vascularization of the solid tumor during its development results in hypoxic (i.e., oxygen deficient) areas within the tumor mass (Moulder, J. L. and Rockwell, S., Cancer Met. Rev. 5: 313-341, 1987; Sartorelli, A. C., Cancer Res. 48: 775-778 (1988)). This inefficient vascularization gives rise to unique problems in the treatment of tumors. For example, inefficient vascularization of solid tumors results in cells that are starved of oxygen and nutrients, and are either noncycling or slowly progressing through the cell cycle. Thus, these cells are relatively resistant to cell cycle-specific chemotherapy and are more difficult to supply with adequate drug concentrations. The oxygen deficiency of these cells further renders them resistant to oxygen-activated agents such as bleomycin and streptonigrin which require the formation of O.sub.2 -derived species in order to be efficacious, and to ionizing radiation whose toxicity is oxygen-concentration dependent. Thus, inefficient vascularization of solid tumors and the resulting subpopulation of hypoxic cells limits the choice of useful and effective chemotherapy treatments.
The resistance of tumor cells to a large number of cancer chemotherapeutic agents has also been correlated with increased intracellular levels of glutathione (GSH) and/or glutathione S-transferase (GST) activity (Stewart, D. J. and Evans, W. K., Cancer Treat. Rev. 16: 1-40 (1989)). Many neoplastic cell lines which have not been subjected to drug selection pressures also have intrinsically high levels of GSH, and relatively high levels of GST activity have been found in a variety of human tumors. It is thought that the protective effects are due to spontaneous and enzyme-catalyzed interactions between the sulfhydryl group of the glutathione molecule and the chemotherapeutic agent. Accordingly, in addition to hypoxia, the resistance of various cell lines and human tumors to a variety of chemotherapeutic agents has been attributed to their high non-protein thiol and GST contents.
Radiotherapy treatments have also been largely unsuccessful in the treatment of solid tumors. Hypoxic cells in particular have proven to be resistant to ionizing radiation since the sensitivity to ionizing radiation is dependent upon the concentration of oxygen.
Solid tumors have been treated with chemotherapy and radiotherapy for many years with limited degrees of success. New potential drugs have been developed to address the problem of chemotherapeutic and radiotherapeutic resistance. For example, several classes of nitro-containing synthetic hypoxia-selective agents have been developed, including analogs of nitroimidazoles (Jenkins, T. C., The Chemistry of Antitumor Agents, Wilman, ed., pp. 342-369, Blackie, Glasgow (1990)), nitroacridines (Wilson, W. R., Denny, W. A., Twigden, S. J., Baguely, B. C. and Probert, J. C., Brit. J. Cancer 49: 215-223 (1984)), benzotriazine N-oxides (Zeman, E. M., Brown, J. M., Lemmon, M. J., Hirst, V. K. and Lee, W. W., Int. J. Radiat. Oncol. Biol. Phys. 12: 1239-1242 (1986)), nitrobenzyl halides and carbamates (Teicher, B. A. and Sartorelli, A. C., J. Med. Chem. 23: 955-960 (1980); Kirkpatrick, D. L., Johnson, K. E. and Sartorelli, A. C., J. Med. Chem. 29: 2048-2052 (1986)), nitrobenzyl mustard quaternary salts (Tercel, M., Wilson, W. R. and Denny, W. A., J. Med. Chem. 36: 2578-2579 (1993); Tercel, M., Wilson, W. R., Anderson, R. F. and Denny, W. A., J. Med. Chem. 39: 1084-1094 (1996)), and nitrobenzyl phosphorodiamidates (Mulcahy, R. T., Gipp, J. J., Schmidt, J. P., Joswig, C. and Borch, R. F., J. Med. Chem. 37: 1610-1615 (1994)). All of these classes of compounds are hypothesized to undergo preferential reductive activation in hypoxic cells to generate potent cytotoxins.
1,2-Bis(sulfonyl)-1-methyl- and 1-(2-chloroethyl)hydrazine compounds shown in formula 1 have been identified that possess antineoplastic activity (Shyam, K., Hrubiec, R. T., Furubayashi, R., Cosby, L. A. and Sartorelli, A. C., J. Med. Chem. 30: 2157-2161 (1987); Shyam, K., Penketh, P. G., Divo, A. A., Loomis, R. H., Patton, C. L. and Sartorelli, A. C., J. Med. Chem. 33: 2259-2264 (1990)). ##STR1##
In formula 1, R.sup.1 and R.sup.2 are alkyl groups or aryl groups, and R is --CH.sub.3 or --CH.sub.2 CH.sub.2 Cl. These compounds are thought to undergo spontaneous decomposition in aqueous media to generate the putative alkylating species RN=NSO.sub.2 R.sup.2. The most active compound of this class is 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (compound 2) and is described in U.S. Pat. No. 4,892,887 to Sartorelli et al.: ##STR2##
Compound 2 has been demonstrated to produce 40% cures of mice bearing the L1210 leukemia when administered as a single intraperitoneal dose (Shyam, K., Penketh, P. G., Divo, A. A., Loomis, R. H., Patton, C. L. and Sartorelli, A. C., J. Med. Chem. 33: 2259-2264 (1990)). However, compound 2 is active only over a narrow dosage range. In addition, compound 2 has a relatively short half-life (30 to 40 seconds at pH 7.4 and 37.degree. C.) and exhibits considerable host toxicity. These disadvantages limit the use of compound 2 as an anticancer agent.
Prodrugs of compound 2 have been synthesized as compounds 3 and 4 (Shyam, K., Penketh, P. G., Loomis, R. H., Rose, W. C. and Sartorelli, A. C., J. Med. Chem. 39: 796-801 (1996); Shyam, K., Penketh, P. G., Divo, A. A., Loomis, R. H., Rose, W. C. and Sartorelli, A. C., J. Med. Chem. 36: 3496-3502 (1993)) and are disclosed in U.S. Pat. Nos. 5,256,820 and 5,637,619: ##STR3##
Both compounds 3 and 4 have broad-spectrum antitumor activity and are considerably less toxic to host animals than compound 2. However, compound 3 undergoes spontaneous decomposition in aqueous media similar to that found with compound 2. Compound 4 is more resistant to spontaneous decomposition in aqueous media, but is prone to nonspecific thiol, protease, and plasma catalyzed activation, a major disadvantage to the therapeutic usefulness of this compound.
Additional N,N'-bis(sulfonyl)hydrazines and related chemotherapeutic compounds are disclosed in U.S. Pat. Nos. 5,281,715; 5,214,068; 5,101,072; 4,962,114; 4,849,563; and 4,684,747.
What is needed in the art is a class of chemotherapeutic agents that efficiently and effectively treats neoplastic cells having resistance to conventional chemotherapeutic agents, is relatively stable, and which minimizes host toxicity. The present invention offers a solution to these needs.